Creating Super Stem Cells for Cardiac and Wound Repair

创造用于心脏和伤口修复的超级干细胞

• 批准号: 7374010
• 负责人: Pampee P Young
• 金额: $ 32.88万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7374010
• 关键词: Address; Biogenesis; Birth; Blood Vessels; Bone Marrow; Cardiac; Cardiac Myocytes; Cell Proliferation; Cell Therapy; Cells; Class; Clinical Trials; Conditioned Culture Media; Data; Deterioration; Development; Down-Regulation; Employee Strikes; Endothelial Cells; Endothelium; Fibroblasts; Functional disorder; Future; Gene Expression; Gene Targeting; Granulation Tissue; Heart; Heart failure; Histologic; Human; Infarction; Injection of therapeutic agent; Intramuscular; Knowledge; Lead; Link; MRL/MpJ Mouse; Mediating; Mesenchymal Stem Cells; Modeling; Molecular; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Natural regeneration; Pathway interactions; Phenotype; Population; Porifera; Pre-Clinical Model; Reagent; Regulation; Relative (related person); Role; Signal Pathway; Signal Transduction; Stem cells; Therapeutic; Therapeutic Intervention; Tissue Model; Tissues; Transcript; Treatment Efficacy; Wound Healing; Wounds and Injuries; base; concept; diabetic; fetal; human SFRP4 protein; improved; improved functioning; member; migration; novel; older patient; paracrine; preclinical study; reconstitution; repaired; research study; self-renewal; stem; tool; transdifferentiation; wound

DESCRIPTION (provided by applicant): Until recently, myocardial loss and associated functional deterioration was regarded as irreversible. Yet, accumulating evidence suggests that injected stem cells can improve function of a failing heart, giving birth to a revolutionary concept of regenerative therapy for the heart. Bone marrow (BM)-derived mesenchymal stem cells (MSCs), known to differentiate into a wide variety of tissues, have shown in several preclinical models to result in improved myocardial function leading to a current human clinical trial to provide these dramatic new cell based therapies using human MSCs for myocardial repair. Hence, understanding how to enhance their therapeutic efficacy, e.g. to develop "super" stem cells, would expand their utility, especially in the elderly, patients with cardiac dysfunction, and in the diabetic population in whom stem cell dysfunction has been described. Using a strain that represents the upper end of the regenerative spectrum we isolated MSCs that demonstrate remarkably enhanced regenerative capacity as compared to those from C57Bl/6 (wildtype, WT) mice. The "super" MSCs demonstrated dramatically increased proliferation, vigorous wound tissue reconstitution, and vascular plasticity in a mouse granulation tissue model. Also, soluble factors derived from these cells caused significantly increased proliferation of fetal cardiomyoctyes and migration of endothelial cells over control conditioned media. In a murine myocardial infarct model, intramuscular peri- infarct injection of these cells showed favorable preliminary functional results over WT MSCs and control. We have identified a striking downregulation of the Wnt pathway in the "super" MSCs by differential expression of members of secreted frizzled related proteins and soluble Wnts as compared to WT. We verified both the relative downregulation of Wnt/-catenin signaling in MRLMSCs and that Wnt pathway inhibition enhanced MSC proliferation and granulation tissue formation, implicating this pathway as the molecular basis for the superior regenerative phenotype. We hypothesize that regulation of the Wnt signaling pathway is critical for MSC self-renewal and regenerative capacity. Moreover, we propose that modulating the activity of this pathway will recapitulate the "super stem cell" phenotype and is an excellent future target for cell based therapies for myocardial injuries and wound regeneration.

描述（由申请人提供）：直到最近，心肌丧失和相关功能恶化被认为是不可逆的。然而，越来越多的证据表明，注射干细胞可以改善衰竭心脏的功能，从而催生了心脏再生疗法的革命性概念。骨髓（BM）衍生的间充质干细胞（MSC）已知分化成多种组织，已经在几种临床前模型中显示出导致改善的心肌功能，从而导致当前的人类临床试验，以使用人类MSC提供这些引人注目的新的基于细胞的疗法用于心肌修复。因此，了解如何提高其治疗效果，例如开发“超级”干细胞，将扩大其效用，特别是在老年人，心脏功能障碍患者和糖尿病人群中，其中干细胞功能障碍已被描述。使用代表再生谱上端的菌株，我们分离了MSC，其与来自C57 B1/6（野生型，WT）小鼠的那些相比显示出显著增强的再生能力。在小鼠肉芽组织模型中，“超级”MSC表现出显著增加的增殖、有力的伤口组织重建和血管可塑性。此外，来自这些细胞的可溶性因子引起胎儿心肌细胞的增殖和内皮细胞的迁移显着增加控制条件培养基。在鼠心肌梗死模型中，肌内注射这些细胞显示出优于WT MSC和对照的有利的初步功能结果。我们已经通过与WT相比分泌的卷曲相关蛋白和可溶性Wnt的成员的差异表达鉴定了“超级”MSC中Wnt途径的显著下调。我们证实了MRLMSC中Wnt/β-catenin信号的相对下调以及Wnt途径抑制增强MSC增殖和肉芽组织形成，暗示该途径是上级再生表型的分子基础。我们假设Wnt信号通路的调节对于MSC的自我更新和再生能力至关重要。此外，我们提出，调节该途径的活性将重演“超级干细胞”表型，并且是用于心肌损伤和伤口再生的基于细胞的疗法的极好的未来靶点。